Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
J Cell Biol. 2022 Mar 7;221(3). doi: 10.1083/jcb.202111095. Epub 2022 Jan 11.
Glycosylphosphatidylinositol (GPI) is a glycolipid membrane anchor found on surface proteins in all eukaryotes. It is synthesized in the ER membrane. Each GPI anchor requires three molecules of ethanolamine phosphate (P-Etn), which are derived from phosphatidylethanolamine (PE). We found that efficient GPI anchor synthesis in Saccharomyces cerevisiae requires Csf1; cells lacking Csf1 accumulate GPI precursors lacking P-Etn. Structure predictions suggest Csf1 is a tube-forming lipid transport protein like Vps13. Csf1 is found at contact sites between the ER and other organelles. It interacts with the ER protein Mcd4, an enzyme that adds P-Etn to nascent GPI anchors, suggesting Csf1 channels PE to Mcd4 in the ER at contact sites to support GPI anchor biosynthesis. CSF1 has orthologues in Caenorhabditis elegans (lpd-3) and humans (KIAA1109/TWEEK); mutations in KIAA1109 cause the autosomal recessive neurodevelopmental disorder Alkuraya-Kučinskas syndrome. Knockout of lpd-3 and knockdown of KIAA1109 reduced GPI-anchored proteins on the surface of cells, suggesting Csf1 orthologues in human cells support GPI anchor biosynthesis.
糖基磷脂酰肌醇（GPI）是一种糖脂膜锚，存在于所有真核生物的表面蛋白上。它在 ER 膜中合成。每个 GPI 锚需要三个乙醇胺磷酸（P-Etn）分子，这些分子来自磷脂酰乙醇胺（PE）。我们发现，酿酒酵母中有效的 GPI 锚合成需要 Csf1；缺乏 Csf1 的细胞会积累缺乏 P-Etn 的 GPI 前体。结构预测表明 Csf1 是一种类似于 Vps13 的管状形成脂质转运蛋白。Csf1 存在于 ER 与其他细胞器之间的接触部位。它与 ER 蛋白 Mcd4 相互作用，Mcd4 将 P-Etn 添加到新生的 GPI 锚上，这表明 Csf1 在 ER 中的接触部位将 PE 输送给 Mcd4，以支持 GPI 锚生物合成。CSF1 在秀丽隐杆线虫（lpd-3）和人类中有同源物（KIAA1109/TWEEK）；KIAA1109 的突变导致常染色体隐性神经发育障碍 Alkuraya-Kučinskas 综合征。lpd-3 的敲除和 KIAA1109 的敲低减少了细胞表面的 GPI 锚定蛋白，这表明人类细胞中的 Csf1 同源物支持 GPI 锚生物合成。
